title: Bronchus-associated lymphoid tissue in pulmonary hypertension produces pathologic autoantibodies.
abstract: BACKGROUND
  Autoimmunity has long been associated with pulmonary hypertension. Bronchus-associated lymphoid tissue plays important roles in antigen sampling and self-tolerance during infection and inflammation.
  
  
  OBJECTIVE
  We reasoned that activated bronchus-associated lymphoid tissue would be evident in rats with pulmonary hypertension, and that loss of self-tolerance would result in production of pathologic autoantibodies that drive vascular remodeling.
  
  
  METHODS
  We used animal models, histology, and gene expression assays to evaluate the role of bronchus-associated lymphoid tissue in pulmonary hypertension.
  
  
  RESULTS
  Bronchus-associated lymphoid tissue was more numerous, larger, and more active in pulmonary hypertension compared with control animals. We found dendritic cells in and around lymphoid tissue, which were composed of CD3(+) T cells over a core of CD45RA(+) B cells. Antirat IgG and plasma from rats with pulmonary hypertension decorated B cells in lymphoid tissue, resistance vessels, and adventitia of large vessels. Lymphoid tissue in diseased rats was vascularized by aquaporin-1(+) high endothelial venules and vascular cell adhesion molecule-positive vessels. Autoantibodies are produced in bronchus-associated lymphoid tissue and, when bound to pulmonary adventitial fibroblasts, change their phenotype to one that may promote inflammation. Passive transfer of autoantibodies into rats caused pulmonary vascular remodeling and pulmonary hypertension. Diminution of lymphoid tissue reversed pulmonary hypertension, whereas immunologic blockade of CCR7 worsened pulmonary hypertension and hastened its onset.
  
  
  CONCLUSIONS
  Bronchus-associated lymphoid tissue expands in pulmonary hypertension and is autoimmunologically active. Loss of self-tolerance contributes to pulmonary vascular remodeling and pulmonary hypertension. Lymphoid tissue-directed therapies may be beneficial in treating pulmonary hypertension.
authors.affiliation: 1 Department of Pediatrics-Critical Care.
authors.forename: Kelley L
authors.initials: KL
authors.lastname: Colvin
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Cripe
authors.forename: D Dunbar
authors.initials: DD
authors.lastname: Ivy
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
authors.forename: Michael E
authors.initials: ME
authors.lastname: Yeager
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity; D001808:Blood Vessels / Q000276:immunology*; D001980:Bronchi; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000276:immunology; D020869:Gene Expression Profiling; D006976:Hypertension, Pulmonary / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D018836:Inflammation Mediators; D008168:Lung / Q000098:blood supply* / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D018836:Inflammation Mediators